TW200815059A - Dosage aerosols for the application of pharmaceutical formulations - Google Patents

Abstract

The invention relates to pharmaceutical active substances, active substance mixtures and formulations for use as an aerosol in propellant-containing [1.1.1.2-tetrafluoroethane (HFC-134a) or 1.1.1.2.3.3.3-heptafluoropropane (HFC-227)] metered-dose aerosols and the metered-dose aerosols for administering these active substances, active substance mixtures and formulations.

Description

200815059 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a propellant containing [1·1·1·2-tetrafluoroethane (HFC-134a) or 1·1·1·2.3·3· a pharmaceutically active substance, an active substance mixture and a formulation as a spray in a 3-heptafluoropropane (HFC-227) metered dose spray, and for the administration of the active substance, the active substance mixture and the formulation A metered dose spray. [Prior Art] • Widely used in the treatment (for example, in the treatment of asthma and diseases causing airway obstruction) by a pressurized, dose-measuring inhaler (MDI, representative, cyanobacteria: inhaler) Delivery of a pharmaceutical spray formulation. Inhalation allows for faster onset of action and minimizes side effects of the body compared to oral administration. Spray can be administered by inhalation or topical application to the nasal mucosa. Formulations. Formulations for administration of a spray using MDI may consist of a solution or suspension. The solution formulation has advantages over suspension formulations because the medicinal composition is completely dissolved in the propellant and Thus, it has a homogeneous nature. The solution formulation also avoids the problem associated with the physical instability of the suspension formulation' and thus ensures a long-term dosing of the dose. In addition, the solution type metered dose spray There is generally no need to add a surfactant. In addition, as disclosed in, for example, U.S. Patent No. 2004/0184994, there is a so-called, suspension π. The administration of MDI depends on the propulsion of the propulsion system used to generate the spray. 119201.doc 200815059 Typically, the propellant is combined with a mixture of right-handed & d 3 carbon compounds (CFC) to accompany the formulation. The dissolved sound, the high-yield freshness of the eucalyptus, the therapeutic pressure and the stability of the characteristics. It is determined that the CFC destroys the environment, because it becomes the earth's odor layer: the original mouth of the consumption, so the environment is being used. Acceptably part of the environmentally harmful cfc propellant in the presence of a fluorinated hydrocarbon propellant sheet J (HFC propellant) or other unchlorinated propellant instead of a mouth spray inhalation formulation. There are many metered dose sprays in U. Agent 'but its measurement accuracy still needs to be improved.

SUMMARY OF THE INVENTION It is an object of the present invention to provide an apparatus having an increased metering accuracy for an active substance, an active substance, or a formulation. The above object is achieved by a device according to the request. Other advantageous features are the subject of the affiliate request. In a first aspect of the invention, the nozzle tube of the device has a passage (8) which has no or almost no dead volume on one side of the meter away from the metered dose spray. The 'dead volume' is defined as a space that protrudes beyond the nozzle hole (9) and thus is not in the direct flow. [Embodiment] The nozzle tube is a component having several functions: suction according to Fig. 5 The mouth tube is functionally composed of a vertical barrel (2), a valve stem socket (5) 'a nozzle hole (9) and a suction nozzle (6). The swallow nozzle tube accommodates the metered dose spray to The column (2) of the nozzle tube is surrounded by the metered dose spray (1), and the stem of the nozzle tube (5) 119201. (Ιος 200815059 closed the valve stem (4) of the metering valve (3) Forming a seal. The nozzle tube column (2) has a space to securely prevent the valve stem (4) from tilting relative to other valve assemblies (3) by limiting the movement of the metered dose spray (this tilt will be to the valve) (3) Harmful function. In addition, the stem socket (5) forms an arch that limits the depth of penetration of the valve stem (4) in the rod socket of the nozzle tube. * The stem socket has a a passage (8), wherein the actual nozzle hole (9) is pressed against the obtuse angle with respect to its vertical axis. For example, for suspension adjustment ^ formulation and suspension, the nozzle hole has a diameter of 0.2-0.6 mm, preferably between 0.5-0.6 mm, and, if used for solution formulation, the nozzle hole has a range between 0.2-0.27 mm Therefore, the active substance formulation liquefied under pressure can be deflected from the opening of the valve stem (7) vertically downwards > 90° and passed to the outside via the nozzle hole (9). The spray cloud is ultimately Producing a transition from the nozzle hole (9) to the nozzle opening (10). The tool portion is substantially more accurately positioned by a conventional injection molding process (including the nozzle needle and the core of the valve stem socket relative to each other) Positioning) to achieve the variation of the nozzle tube as described in the present invention. Example of stem size: Valve/manufacturer stem diameter Outer diameter of the stem opening Bespak, BK357 3.17 ± 0.01 mm 2.12 ± 0.03 mm Valois, DF31/50RCU 3.19 soil 0·01 mm 1.48 soil 0·02 mm 3M, Neotechnic 2, 76 ± 0·01 mm 1.68 ± 0.04 mm In the second aspect of the invention, the passage (8) is via a nozzle hole ( 9) 119201.doc 200815059 connected to a nozzle opening of a funnel structure It will be apparent from the description of the specification that a suitable dose of the active substance or formulation may be administered in a single dose. The device according to the invention is suitable for use as a pharmaceutically effective active substance or a remedy for a mixture of any suitable active substance 1

Examples of the biological shell mixture or formulation (medical preparation) include all of the inhalable macromolecules disclosed in the European Patent No. 003 478. Preferably, an active substance, an active substance mixture or a formulation for treating a respiratory condition, forgetting a disease by inhalation, or the like is used. The compounds listed below can be used in the device of the invention, alone or in combination. Among the compounds mentioned below, the pharmacologically active substance is selected from, for example, the following substances: betamimetic, anticholinergic, adrenocortical steroid, pDE4_inhibitor,ltd4 _ Antagonists, EGFR-inhibitors, dopamine agonists, m_antihistamines, PAF-antagonists, and PI3-kinase inhibitors. In addition, the trade double or triple restructuring

Combinations can be combined and used in the device of the invention. The combination of w may be, for example, ····W indicates a combination of betamethine with an anticholinergic drug, an adrenocortical steroid, a PDE4-inhibitor, an EGFR inhibitor or a LTD4 antagonist, Combination of cholinergic drugs with betamethine, adrenal corticosteroids, PDE4-inhibitors, EGFR-inhibitors or LTD4-antagonists, -W for adrenal corticosteroids and Pde4-inhibitors, EGFR-inhibition 119201. Doc 200815059 A combination of a agent or a LTD4-antagonist, -W represents a combination of a PDE4-inhibitor and an EGFR-inhibitor or a LTD4-antagonist, and -W represents a combination of an EGFR-inhibitor and a LTD4-antagonist. Preferably, the compound used as the betamethine is selected from the group consisting of salbutamol, arformoterol, bambuterol, bitolterol, bromine σ Broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, tributanol Ibuterol, isoetharine, isoproterenol, levo-salbutamol, mabuterol, meluadrine, isoproterenol, isoproterenol, ° Pibuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, samote Salmeterol, soterenol, sulphonterol, t-butyl epinephrine, 0 tiaramide, tolubuterol, net Zinterol, CHF-103 5, HOKU-81, KUL-1248 and -3-( 4-{6-[2-carbamic 2-(4-carbyl-3-methyl-phenyl)-ethylamino]-hexyloxybutyl]-benzyl-continuous amine; -5 -[2-(5,6-diethyl-diazin-2-ylamino)-1-yl-ethyl-ethyl]-8-yl-l-Η-喧^ scare ^ 2 - -4-Woki- 7_[2-{[2_{[3-(2-phenylethoxy)propyl] dianthranyl}ethyl]-amino}ethyl]-2(3Η)- Benzothiazolone; 119201.doc -10 - 200815059 (2fluoro-4-'ylphenyl)_2 and (1_benzimidazolylmethyl-2-butanylamino)ethanol; soil 1 [3 (4•A 'oxy]ylamino)_4·transphenylyl]·2-[4·(1·benzoxazolyl)-2-methyl_2_butylamino]ethanol; ', -H2H-5m oxygen Generation _4, 4 benzopyrene _8_ kib 2 cases of heart N,N-dimethylaminophenyl)_2_methyl_2-propylamino]ethanol; _ W2H-5- Base·3_oxo_4h], 4_benzoxene_8_yl]_2♦(4)methoxyphenyl)-2.methyl-2-propylamino]ethanol; • - 1-[ 2Η·5·(4)-3.oxo-4H], benzophenanthene-t-butyloxyphenyl)-2-methyl-2-propylamino]ethanol; -1_[2Η-5_ Hydroxy-3-oxo-4H_M_benzoindole 8_yl]_2_{4_[3_(4_methoxyphenyl)-1,2,4_three -3-yl]_2_mercapto-2-butylamino}ethanol; -5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)_2H-1,4-benzopyrene Oral-3-(4H)-one; 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tris-butylamino)ethyl alcohol; -6- Hydroxy-8-{l-hydroxy·2-[2-(4-methoxy-phenyl)·ι,ι-dimethyl-ethylamino]-ethyl}·4Η-stupid [1, 4] slogan _ _3_ ketone; _ 6·hydroxy-8-{l-hydroxy-2-[2-(ethyl-4-phenoxy-acetic acid)-1,1-dimethyl-ethylamine ]-Ethyl}-4H-benzo[1,4]indole-3-one; -6-hydroxy-8-{buhydroxy-2-[2_(4-phenoxy-acetic acid)-i,l - Dimercapto-ethylaminol l·ethyl}·4Η_benzo[1,4]噚耕_3_ ketone; -8-{2-[1, 卜二曱基_2-(2, 4·6-trimethylphenyl)-ethylaminol l-hydroxyl 119201.doc -11- 200815059 base-ethyl}-6-hydroxy-4H-benzo[1,4]噚耕-3- Ketone; -6-hydroxy:yl-perylene-2-[2_(4-trans-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4Η-benzo[1 , 4] indole-3-one; -6-trans-yl-1-yl-based 2-[2-(4.isopropylphenyl)-1,1 dimethyl-ethylamino]- Ethyl}-4Η-benzo[1,4]indole-3-one; -8-{2-[2 -(4-ethyl-phenyl)-1,1-dimercapto-ethylamino]-1-yl-ethyl-ethyl 6-hydroxy-4-indole-benzo[1,4]indole-3 -keto; -8-{2-[2-(4-ethyl-phenyl)-1,1-dimercapto-ethylamino]-1-yl-yl-ethyl group 6-hydroxy-4Η -benzo[I,4]morphin-3-one; • 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2Η- Benzo[1,4][0,8-yl)-ethylamino]-2-indolyl-propyl}-phenoxy)-butyric acid; -8-{2-[2-(3) ,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4Η-benzo[1,4]唠耕-3- Ketone; -1-(4-ethyllacyl-amidyl-3-methyl-5-phenyl)-2-(tris-butylamino)ethanol; ^ - 2 -pyridyl-5 - (1. mercapto-2-{2-[4-(2-propionyl-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyde; - N-[2-hydroxy-5-(1-hydroxy-2.{2-[4-(2-hydroxy-2-phenyl-ethylamino)-.phenyl]-ethylaminoethyl) Phenyl]-formamide; -8-3⁄4 base-5-(1-carbyl-2-(2-[4-(6-methoxy-biphenyl-3-ylamino)) benzene ]]-mercaptoamino}-ethyl 1 Η -喧琳-2 阙, -8-hydroxy-5-[1-hydroxy-2-(6-phenethyl Amino-hexylamino)-ethyl]-1 quinone-quinolin-2-one; 119201.doc -12- 200815059 -5-[2-(2-{4-[4-(2-amino-2) - mercapto-propoxy)-phenylamino]-phenylethylamino)-1-hydroxy-ethyl]hydroxy-1H-quinolin-2-one; -[3-(4-{6- [2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxybutyl]-5-methyl-phenyl]-urea; -4-(2 -{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino-p-hydroxy-ethyl)-2-hydroxymethyl-phenol; _ 3-(4 -{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-phenylmethylxanthine; _ 3 -(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzoxanthine -4-(2-{6-[4-(3-cyclopentanesulfonyl-phenyl)-butoxy]-hexylaminopyridin-1-yl-ethyl)-2-thiol Benzene; -N-adamantane-2-yl-2-(3-{2-indolyl-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl }-Phenyl)-acetamide;- as it is required to be in the form of its racemic isomer, enantiomer, diastereomer and, if desired, pharmacologically acceptable The acid addition salts, or in the form of fusion of the hydrate. According to the present invention, the acid addition salt of the betamethine is preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, methanesulfonic acid. Salts, nitrates, maleates, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates and p-toluenesulfonates. The anti-cholinergic test drug is preferably selected from the group consisting of tiotropium salt (preferably, desertified salt) and oxyxanthium salt (more ' ' ' &gt a stinky salt, a flutr〇pium salt (preferably, desertification 119201.doc -13-200815059 salt), an ipratropium salt (preferably, a bromide salt), Glycopymmhmi salt (preferably, bromide salt), trsospium salt (slightly 'chlorinated salt'), tolterodine (t〇iter〇dine). Among the salts described above, 1% is a pharmacologically active ingredient. In terms of anions, the above salts preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, sulphate, Tartrate, oxalate, succinate, benzoate or p-toluene sulphate' is a preferred counterion for chloride, bromide, carbon, sulfate, methanesulfonate or p-toluenesulfonate. Chloride, bromide, iodide and methanesulfonate are especially preferred for all salts. Other preferred anti-cholinergic drugs are selected from the salt of formula AC-1.

Wherein X- indicates an anion having a negative charge, preferably an anion selected from the group consisting of cesium, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate , acetate, citric acid, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, especially preferably bromide, which may be racemic isomerized as desired In the form of a body, an enantiomer or a hydrate. Especially important are the pharmaceutical combinations containing the enantiomers of the formula AC-1-enantiomers. 119201.doc -14- 200815059

AC-1-enantiomer wherein X may have the meanings indicated above. Other preferred anticholinergic drugs are selected from the salt of formula AC-2

Wherein R represents a decyl or ethyl group, and wherein χ· may have the above meaning. In an alternative embodiment, the compound of formula AC_2 may also be present as free base AC.

Other specific compounds are: -2,2-diphenylpropionic acid tropin ester methyl bromide; _ 2,2-diphenylpropionic acid sterol ester methyl bromide; -2-fluoro-2,2-diphenyl Base-acetic acid sterol ester methyl bromide; 2 gas-2,2 - ^-styl acetate tropinol ί 甲甲甲' _ 3,3,,4,4,-tetrafluorodiphenyl glycolic acid tropine Alcohol ester methyl bromide, • 3,3',4,4'-tetrafluorodiphenyl glycolic acid, terpene alcohol® armor/odor H9201.doc -15- 200815059 -4,4'-difluorodiphenylethanol Tetrolol ester methyl bromide; -4,4"-difluorodiphenyl glycolic acid sterol ester methyl bromide; -3,3f-difluorodiphenyl glycolic acid tropin ester methyl bromide; -3, 3'-difluorodiphenylglycolic acid sterol ester methyl bromide; -9-hydroxy--9-decanoic acid tropin ester 曱 bromine; -9-fluoro-苐-9-carboxylic acid tropin ester A Bromine; '-9-hydroxy-hydrazine-9-antimonic acid ester oxime bromide; -9-fluoro--9-formic acid terpene ester methyl bromide; # - 9-methyl-苐-9-曱Acid tropinol ester methyl bromide; -9-methyl-tert--9-decanoic acid sterol ester methyl bromide; - triphenyl glycolic acid cyclopropyl tropine methyl bromide; -2,2-diphenyl propyl Acid cyclopropyl tropoate 曱 bromine; -9-hydroxy-xanthene-9-carboxylic acid cyclopropyl Tropyl ester 曱 bromine; • 9-methyl-苐-9-decyl decyl tropate methyl ester; -9-mercapto-xanthene-9-formic acid cyclopropyl tropine methyl bromide; -9 - thio- -9-formic acid propyl benzoate vinegar >odor; • 4,4'-difluorodiphenyl glycolic acid cyclopropyl tropate 曱 bromine; -9-hydroxy-xanthene -9-Troponic acid ester 曱 bromine; • 9-hydroxy-xanthene-9-formic acid terpene ester methyl bromide; . -9-mercapto-xanthene-9-decanoic acid tropin ester methyl bromide -9-mercapto-xanthene-9-formic acid terpene ester methyl bromide; -9-ethyl-xanthene-9-decanoic acid tropin ester methyl bromide; -9-difluorodecyl-xanthene -9-Troponic acid ester methyl bromide; -9-hydroxydecyl-xanthene-9-antimonic acid terpene ester methyl bromide. 119201.doc -16- 200815059 Within the scope of the present invention, the above-mentioned compounds can also be used as a salt, wherein in addition to the methyl bromide, the salt can be used as a methyl double, wherein the oxime can have a sputum of 7 kg Give the meaning. As the adrenocortical steroid, a compound selected from the group consisting of beclomethasone, betamethasone, budesonide, butix 〇c〇rt, is preferably used. Dclesonide, deflazacort, dexamethas_, etiprednol, flunisone Hde, fluticasone, clopidogrel诺 (lotepredn〇1) 'm〇metas〇ne, prednisolone, prednis〇ne, reflpomde, triamcin〇1〇 Ne), RpR i〇654i, 126, ST-26 and -6,9β difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyloxo-androsteradiene -17-thiocarbonyl acid (S) fluoromethyl ester _ M-diH yl group _16 methyl _3 oxo] 7 propyl methoxy male solid _ • diene · 17 · thiocarbonyl acid (S)-(2.oxo-tetrahydrofuran-3S·yl)ester, _ 6〇C, 9a_difluoro_U-hydroxy- 16α•methyl-3-oxo-17〇1_(2, 2,3,3_Tetramethyl%propylcarbyl)oxy-androgen·14-diene-ΐ7β_formic acid The methyl ester is optionally in the form of its racemic isomer, enantiomer or diastereomer, and optionally in the form of its salts and derivatives, its solvates and/or hydrates. . Any reference to a steroid includes reference to one of its possible salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids may be: alkali metal salts (eg sodium and potassium salts), mercaptophthalic acid salts, phosphates, isonialtleric acid salts, acetates, dichloroacetic acid, propionic acid 119201 .doc -17 - 200815059 Salt, dihydrogen phosphate, palmitate, pivalate or citrate. The PDE4-inhibitor which can be used is preferably selected from the group consisting of enprofylline, theophylline, roflumilaste, ariflo, cilomilast. , tofimilaste, pumafentrine, lirimilaste, arofylline, atizorame, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD_12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CM018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and -N-(3,5-dichloro-I-oxo-purin-4-yl)·4·dione Lacto- 3- 3⁄4 propyl methoxybenzamide; (-)p-[(4aR*,l〇6S*)-9-ethoxy-1,2,3,4,4 mad, 1013 - hexahydro-8-decyloxy-2-methylbenzo[s][l,6]naphthyridin-6-yl]isopropylbenzoguanamine; -(R)-(+)-l- (4-alkaline group)·4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-° ratio of each fluorenone; -3-(cyclopentyloxy-4) -nonyloxyphenyl)-1-(4-Ν'-[indol-2-cyano-S-indenyl-isothioureido] -2_pyrrolidone; -cis [4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]; Leti-4-ranyl-4-(3-cyclopropylmethyllacyl-4-monohaloxyphenyl)cyclohex-butanone; 119201.doc -18 - 200815059 - cis [4-carbyl- 4-(3-cyclo(methylmethoxymethoxymethoxyphenyl)cyclohexane-1-ol]; _ [4-(3-3⁄4-pentyloxy-4)methoxyphenylpyrrolidine_ 2_subunit]acetic acid (R)-(+)-ethyl ester; -[4-(3-cyclopentyloxymethoxyphenyl)pyrrolidine_2_ylidene]acetic acid (S) - (-)-ethyl vinegar; -9-3⁄4 pentyl-5,6·dihydro-7-ethyl_3_(2_thienyl)-9-dan-pyrazole[3.本c]_ 1, 2,4-tris-[4,3-ap ratio bite; -9-% mercapto-5,6-dihydro-7-ethyl-3-(3-tert-butyl)-9-pyrazole And [3.4-c]-l,2,4·triazolo[4.3-a]pyridine; if desired, in the form of a racemic isomer, enantiomer or diastereomer thereof, It may be in the form of its pharmaceutically acceptable acid addition salt, its solvate or hydrate, as appropriate. According to the present invention, the acid addition salt of the pDE4 inhibitor is preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, methanesulfonate, nitrate. , maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate. The LTD4-antagonist used is preferably a compound selected from the group consisting of: montelukast, pranlukast, zafirlukast (2 also! *1111^〇,]\4<;:(%847(20-3523),]^]^0〇1,]^1^91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and _1-((( Han)-(3-(2-(6,7-Difluoro-2-quinolinyl)vinyl)phenyl)_3_(2_(2·hydroxylpropyl)phenyl)thio)methylcyclopropane- Acetic acid; 1-(((1(R)-3(3-(2-(2,3_) gas ϋ 并 并 [3,2-b] ° ratio -5-5·yl)-(E)_ 11920I. Doc •19· 200815059 vinyl)phenyl)_3-(2-(l-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid; -[2-[[2 -(4-Tertiary-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid; optionally as a racemic isomer, enantiomer or a form of a diastereomer, and optionally in the form of a pharmaceutically acceptable acid addition salt, a solvate and/or a hydrate thereof. According to the present invention, the acid addition salt is preferably selected from the group consisting of Among the following: ': hydrochloride, hydrobromide, hydroiodide, sulfate, Acid salts, methane sulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates and p-toluenesulfonates. The term can be used to form a LTD4-antagonist salt or derivative. For example, a metal salt (such as copper or potassium salt), a soil metal salt, a benzoate, a sulphate, an acid test Salt, acetate, propionate, dihydrogen phosphate, palmitate, neodecanoate or citrate. The EGFR-inhibitor which can be used is preferably a compound selected from the group consisting of: citrinizumab (cetuximab), trastuzumab, ABX-EGF, Mab ICR-62 and -4-[(3-chloro-4-fluorophenyl)-amino]-6-{[4-(啉-4-yl)-1-oxo-2-butan-1-yl]amino}-7-cyclopropylmethoxy-啥 琳 ;; 4·[(3-chloro-4-fluorobenzene -amino]-6-{[4-(N,N-diethylamino)+oxo-2-buten-1-yl]aminopurine 7·cyclopropylmethoxy-quin -4-[(3 - gas_4_fluorophenyl)amino]-6-{ [4-(Ν,Ν_dimethylamino oxo-butan-1-yl]amino} -7-cyclopropylmethoxy-啥Salina; 1 19201.doc -20- 200815059 -4-[(R)-(l-Phenylethyl)amino]_6-{[4_(morpholine-4-yloxybuten-1-yl; μamine _7_cyclopentyloxy-oxazoline; _ 4-[(3-chloro-4-a-phenyl)amino]_6-{[4-((r)_6_methyl_2_oxygen _[morpholine-4-yl)-1-oxo-2-buten-1-yl]aminophenyl 7-cyclopropylmethoxy-quino-β-supplied; -4-[(3-chloro-4) _Fluoro-phenyl)amino]_6·{[4-((8)-6...methyl_2_oxo-morpholin-4-yl)oxy-2-oxan-2-yl]aminopurine 7_ [(s)_(whydropyranyl)-oxy]-啥σ sitting; • 4_[(3_chloro-4-a-phenyl)amino]_6_{[4_((κ)-2 _曱oxymethyl_6_oxo-morpholine·4-yl)-1_oxo-2-butene_丨_yl]aminobicyclopropylmethoxy-喧Salina; -4 -[(3-chloro-4-fluoro-phenyl)amino]_6_[2_((8)-glycolyl-2-oxo-ocyl- 4-yl)-ethoxy]-7-methoxy- Quinazoline; 4-[(3-chloro-4-ylfluorophenyl)-amino]_6_({4-[n-(2-decyloxy-ethylmethyl-amino)-1-oxo 2-butene-l-yl}amino)-7-cyclopropylmethoxy 啥 啥 ;; -4-[(3- gas-4·fluorophenyl)amino]_6·{[4&lt ;_(Ν,Ν-dimethylamino•oxo-2·buten-1-yl]aminophenyl 7-ring Pentyloxy- π quetiapine; _ 4-[(R)-(l-phenyl-ethyl)amino]_6_{[4_(Ν,Ν-double gas 2_methoxy-ethyl) -amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl decyloxy _ 啥 琳 ;; • 4-[(R)-(1 phenyl _ B Amino]-6-({4-[Ν-(2-methoxy-ethyl)-Ν-ethyl-amino]-1-oxo-2-buten-1-yl}amino group - 7_cyclopropyl decyloxy _ 喧 琳 琳; 119201.doc -21- 200815059 -4-[(R)-(l-phenylethyl)amine ρ6_({4·[Ν_(2_ Methoxy-ethylmethyl-amine-based io-oxo-2-butene-i-yl}amino)_7_cyclopropylmethoxy _ 喧 琳 ;; 4-[(R)_(l ·Phenyl-ethyl)amino]_6(卜[Ν_(tetrahydrofurfuryl)_Ν_methyl-amino]-1-oxo-2-butene-1 gastric base}amino)_7· Cyclopropylmethoxy _ 啥嗤 Lin; -4-[(3-Ga-4-fluorophenyl)amine phenyl 6][4_(Team 1^_dimethylamino)_1_oxo-2 -buten-1-yl]amino}_7_((and)_tetrahydrofuran-3-yloxy)-quinazoline; _ 4-[(3_chloro-4-fluorophenyl)amino]_6_ {[4_(Ν,Ν-dimethylamino)-1_oxo-2-buten-1-yl]amino}_7(s)_tetrahydrofuranyloxyquinazoline; -4-[ (3-chloro-4-phenyl phenyl) Aminobutyn 2_methoxy-ethyl)_N-methyl-amino]-1-oxo-2·buten-1-yl}amino)_7·cyclopentyloxy-quinazoline φ - 4·[(3_Chlorofluorophenyl)-amino]-6-{[4-(Ν-cyclopropyl-methyl-amino)-1-oxo-2-butene-1 -yl]-aminophenyl 7-cyclopentyloxy-quinazoline; _ 4_[(3_chloro-4.fluorophenyl)amino]_6_{[4_(Ν,小dimethylamino) Oxy-2-non-1-yl-1-yl]aminophenyl 7-[(R)_(tetrahydrofuran-2-yl)methoxy]·啥吐琳; -4-[(3·气-4- Fluorophenyl)amino]_6_U4_(n,n-dimethylamino)]•oxo-2-butene-1-yl]aminopyr 7-[(S)-(tetrahydrofuran-2-yl)anthracene Oxy]_ 啥 琳 琳; • 4-[(3-ethynyl-phenyl)amino]_67_bis-(2_methoxy-ethoxy quinoxa 119201.doc -22- 200815059 琳琳; 4-[(3-chloro-4-fluorophenyl), amino (morpholine-4)-propoxy]_6_[(vinylcarbonyl)amino]-quinazoline; -4-[( ((Phenyl-ethyl)amino] winter (heart hydroxy-phenyl)_7Η_咣 并[2,3-d] sneeze; -3 -cyano-4-[(3-chloro-4) -1phenyl)amino]-6-{[4·(Ν,Ν-dimethylamino)-1-oxo-2-buten-1-yl]aminophenyl 7-ethoxy -Quinoline; -4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]aminodibu 6-(5·{[(2-methane saponin-ethyl)amine _ 4-[(R)-(l-phenylethyl)amino]-6-{[4_((κ)-6-mercapto-2 _Oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]aminopurine 7-methoxy-quinazoline; -4-[(3-chloro-4- Fluorophenyl)amino]-6_{[4·(morpholine_4_yloxy-2-_2-buten-1-yl]-amino}_7_[(tetrahydrofuran-2-yl)methoxy]-quin Oxazoline; -4-[(3-chloro-4-fluorophenyl)aminophenyl 6_({4-[n,N-bis-(2-methoxy-ethyl)- fine base] 1 oxo -2 - butyl-1-yl}amino)-7-[(tetrachloromethane-2-yl) methoxy l. quinazoline; -4-[(3-ethynyl-phenyl)amine Base]_6_{[4_(5·5_dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]aminobuquinazoline; '[(3_Chloro_4_fluoro-phenyl)amino]]6-[2-(2.2-dimethyloxy-morpholin-4-yl)-ethoxy]_7-methoxy- Quinazoline; _ 4-[(3-Ga-4-fluoro-phenyl)aminoj•dimethyl-cardioxo-morpholin-4-yl)-ethoxy]_7_[(ΚΗθhydrofuran) _2_yl) methoxy quinazolin, _ 4_[(3-chloro-4-fluoro-phenyl) Amino]_7-|>(2·2_dimethyl-cardiooxin-?119201.doc -23- 200815059 lin-4-yl)-ethoxy]-6-[(S)-(four Hydrogen 12 fut-2-yl) oxime] 啥 olfactory, -4-[(3-chlorophenyl)amino]-6-{2_[4-(2-deutero-morpholinyl) Hexahydropyranyl-1 -yl]-ethoxy}-7-decyloxy-indenyl; -4_[(3-chloro-4-fluoro-phenyl)amino]-6-[1- (t-butoxycarbonyl)·hexaqi-azino-4-yloxy]-7-methoxy-quinoxaline; -4-[(3-chloro-4-fluorophenyl)amino] -6-(trans-4-aminocyclohexyl-1-yloxy)·7-methoxy-quinazoline; • 4-[(3-chloro-4-fluoro-phenyl)amino group -6-(trans-4-methanesulfonylamino-cyclohexyl-buyloxy)-7-methoxy-quinazoline; -4-[(3-chloro-4-fluoro-phenyl) Amino]-6-(hexahydrooxaridin-3-yloxy)-7-methoxy-indenyl; -4-[(3-chloro-4-fluoro-phenyl)amino]- 6-(1-ethyl-hexahydroσ ratio -4-aminooxy)-7-methoxy-oxime; -4-[(3-chloro-4-fluoro-phenyl)amino] -6-{1-[(morpholin-4-yl)carbonyl]-hexahydroacridin-4-yloxy}-7-methoxy-quinazoline; Lu-4-[(3_chloro- 4-fluoro-phenyl)amino] winter {1-[(methoxymethyl)carboxy]-hexahydro Pyridin-4-yloxy}-7-decyloxy-quinazoline; '-4-[(3·chloro-4-fluoro-phenyl)amino]-6-(hexahydro- 0-pyridine-3 - methoxy) 曱 曱 • 基 基 基 4-[(3-chloro-4-"-phenyl)amino]-6-[l-(2-ethyl-amino-yl-B -), hydrogen pyridin-4-yl-oxy]_7-methoxy-quinazoline; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(four Hydroquinone-4-yloxy)-7-ethoxy-啥嗤琳; 119201.doc -24- 200815059 _ 4-[(3-Gas-4-fluoro-phenyl)amino]-6- ((S)-tetrahydrofuran_3_yloxy)_7_hydroxy-quinazoline; _ 4-[(3- gas-4-a-phenyl)amino]-6-(tetrahydropi-pyridyloxy) )7-(2_Ethylamino-ethoxy)-喧唆琳; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{anti-4_[(two Methylamino)sulfonyl-amino]-cyclohex-1-yloxy}-7-methoxy-hydrazine; -4-[(3-chloro-4-fluoro-phenyl)amino ]-6-{cis-4-[(cylinyl)carbonylamino]-cyclohex-1-yloxy}-7-methoxy-喧 琳; 4-[(3_氯-4_ I -phenyl)amino]-6-{trans-4-[(Nylin+yl)sulfonylamino]•cyclohex-1-yloxy}-7-methoxy-quinazoline; 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydrogen) U-pyranyl-4'-yloxy)-7-(2-acetamidoamino-ethoxy)-quinazoline; -4-[(3-chloro-4-indolyl)amino] -6-(tetrahydropi-pyranyloxy)_7_(2_methanesulfonylamino-ethoxy)-quinazoline; -4-[(3-chloro-4-fluoro-phenyl)amine ]]-6-{1-[(hexahydrou 唆 唆 small) carbonyl]_ hexahydro σ than -4-yloxy}-7-methoxy-isophilic; -4-[(3 -chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-hexahydropyridine-4-yloxy)-7-methoxy-quinazoline; -4·[(3 - Chloro-4-1-phenyl)amino]-6-(cis-4-{Ν_[(tetrahydrogen).比喃_4_基) Weiji]-Ν-methyl-amino}-defen-1-yloxy)-7-decyloxy_啥吐琳; -4_ [(3-chloro-4- Fluoro-phenyl)amino]-6-(cis-4-{N-[(Merlin-4-yl)-yl]-N-methyl-amino}-cyclohex-1-yloxy) -7_methoxy-isophilic; 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis.4-{Ν-[(morpholine-4)-) Sulfhydryl]-fluorene-methyl-amino}-cyclohex-1-yloxy)-7-methoxy, hydrazine; 119201.doc -25- 200815059 -4-[(3-chloro- 4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohex-1-yloxy)-7-decyloxy-quinazoline; •4-[ (3-chloro-4-1_phenyl)amino]-6-(1_methyl sulphide _ hexahydro 11 唆 4-yloxy)-7-ethoxy- 喧嗤 ;; -4-[(3-Gas-4-1_phenyl)amino]·6-(1-methyl-stone yellow-branched-hexahydro-11-pyridyl_4_yloxy)-7-(2·A Oxy-ethoxy)-quinazoline; -4-[(3-chloro-4_p-phenyl)amino]-6-[1-(2-methoxy-ethenyl)-hexa Hydropyridin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline; -4-[(3-chloro-4-ylphenyl)amino]-6-( Cis-4-ethionylamino-cyclohexyl-1_yloxy)-7-methoxy-quinazoline; -4-[(3- Ethynyl-phenyl)amino]-6-[1-(t-butoxycarbonyl)-hexahydroacridine-4-yloxy]-7-methoxy-quinazoline; -4-[ (3-ethynyl-phenyl)amino]-6-(tetrahydron-pyran-4-yloxy)_7-methoxy-quinoline; -4-[(3- gas-4-IL -phenyl)amino]-6-(cis-4-{Ν-[(hexahydro-sigma-1)-] carbyl] fluorenyl-amino}- 哀 己-1-quot; Benzyl-7-methoxy-hydrazine; -4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{>^[(4_methyl) -Bistazin-1-yl)-carbonyl]-fluorenyl-mercapto-amino}-cyclohex-1-yloxy)-7-methoxy-quinazoline; _ 4-[(3-chloro- 4-fluoro-phenyl)amino group >6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohex-1-yloxy}·>methoxy-quinazoline Phenanthine; -4-[(3.sup.4-fluoro-phenyl)amino]-6-{H(2-oxo. piroxime) ethyl]-hexahydropyridine _4-oxygen Keb-carbyl-carbazole; -4-[(3_ -4-fluoro-phenyl)amino-based MOU morpholine _4-yl) benzyl]• hexahydro H9201.doc -26 - 200815059 pyridine -4-yloxy}-7-(2-decyloxy-ethoxy)-quinazoline; -4-[(3-ethylidyl-phenyl)amino]-6-(1-B Mercapto-hexahydroindol-4-yloxy)-7-A啥-啥Wahlin; -4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-hexahydropyridin-4-yloxy)-7-methoxy-啥峻Lin; -4- [(3-ethylidene-yl)amino]-6-(1-indenyl-6-pyrene-pyrene-4-yloxy)-7-decyloxy-喧Salina -4-[(3- gas-4-is-phenyl)amino]-6-(1-methyl-hexahydro-port ratio sigma-4-yloxy)-7(2-methoxy -Ethyloxy)-n-quine n-isoline; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-hexahydroindan-4-yloxy -7-methoxy-hydrazine; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-nonylamino-cyclohexan-1-yl Oxy)-7-methoxy-hydrazine; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[]^-(2-oxo -Acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}_7-decyloxy-quinazoline; -4-[(3-ethynyl-phenyl)amino] -6-(hexahydron 唆 唆 4 4 4 4 ) ) ; ; ; ; ; ; -4- -4-[(3-ethynylphenyl)amino]-6-[1-(2 _Methoxy-ethenyl)-hexahydro-pyridin-4-yloxy]-7-methoxy-quinazoline; . 4- 4-((3-ethynyl-phenyl)amino] winter {1-[(morpholine-4-yl) Daigi]-hexahydro! 1 than bite-4_yloxy }-7 -Methoxy-oxime. Sitting lin; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis_2,6-didecyl-morpholine-4-yl)13⁄4yl]- Six gas σ σ -4- -4-yloxy}-7-methoxy-isophilic; -4-[(3- gas _4-fluoro-phenyl)amino]]6-{1-[( 2_曱基-吗淋_4_基)carbonyl 119201.doc -27- 200815059 base]-hexahydroacridin-4-yloxy}-7-decyloxy-quinazoline; -4-[( 3-chloro-4- gas·phenyl)amino]-6-{l-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]-g- 5-yl)carbonyl]-hexahydroacridine_4_yloxy}·7-decyloxy- 啥°坐琳; -4-[(3-chloro-4-a-phenyl)amino]- 6-{ 1-[(Ν-Methyl-Ν-2.methoxyethyl-amino)benzyl]-hexahydroindol-4-yloxy}-7-methoxy-isophilic -4-[(3-Gas-4-fluoro-phenyl)amino]-6·(1 _ethyl-hexahydroπ-biti-4-yloxy)-7-methoxy-quinazoline Benzene; -4-[(3-Gas-4-1-phenyl)amino]-6-{1-[(2-methoxyethyl)-Weibub hexanitro- 0 唆-4-yloxy }-7-methoxy-啥 琳 ;; -4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(3-methoxypropyl-amino) )-carbonyl]-hexahydro 13-p--4-yloxy}-7-decyloxy- π-ku σ sitin; -4_[(3-chloro-4-fluorophenyl) Amino]-6-[Shun "·4·"(Ν-甲烧石黄醯基-Ν-Methyl-Amino)-D-hexyl-1 -yloxy]-7-methoxy-啥Salina -4-[(3- gas-4-fluorophenyl)amino]-6-[cis-4-(anthracene-acetamido-amino)-cyclohex-1-yloxy]-7 - 曱oxy-啥嗤琳; -4-[(3- gas-4-fluoro-phenyl)amino]-6-(trans-4-indolyl-cyclohexyl-ι-yloxy)- 7-decyloxy-indole; 4-[(3_gas-4-fluorophenyl)amino]-6-[cis-4-(N-methylsulfonyl-N-methyl-amine )-cyclohex-1-yloxy]-7-methoxy-quinazoline; -4-[(3- gas-4-oxo-phenyl)amino]-6-(trans-4- Di-ammonium-cyclohexyloxy)-7-methoxy-hydrazine; _ 4-[(3·chloro-4-fluoro-phenyl)amino]-6-(anti-4- {N-[(morpholine-4-yl)carbonyl]·N-methyl-aminobicyclohexyl-yloxy)-7-methoxy-quinazol; 119201.doc -28 - 200815059 -4 -[(3-chloroIfluoro-phenyl)amino]-6_[2_(2,2-dimethyloxazolin-4-yl)-ethoxy]_7_[(s)_(tetrahydrofuranyl) Methoxy]-quinopaline; -4-[(3-chloro-4-hydroxy-1-phenyl)amino]_6_(1-ethyl-hexahydroacridine-4-yloxy)-7-曱oxy-quinazoline; -M(3-chloro-4-fluoro-phenyl Amino]·6_(1-cyano-hexahydropyridine-4-yloxy)-7-methoxy-quinazoline; as it is required to be a racemic isomer, enantiomer, non The form of the enantiomer is 'in the form of its pharmacologically acceptable acid addition salt, solvate or hydrate. According to the invention, the acid addition salts are preferably selected from the group consisting of hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, decane sulfonates, nitrates, horses. Acid salts, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates and p-toluenesulfonates. The dopamine agonist used is preferably selected from the group consisting of: bromocriptin, cabergoline, (alpha-dihydroergocryptine, ergot) Lisuride, thiopropyl ergoline (perg〇Hde), pramipexol, 克克口丨丨(r〇xind〇i), 累匹利洛(r〇pinir〇i) , talipexol, tergurid, and viozan, in the form of their racemic isomers, enantiomers, diastereomers, as needed, and if desired, pharmacologically An acceptable form of an acid addition salt, a solvate or a hydrate. According to the invention, the acid addition salts are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroquinone, Sulfate, sulphate, methyl 119201.doc -29- 200815059 sulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , benzoate and p-toluenesulfonate.

The H1-antihistamine which can be used is preferably a compound selected from the group consisting of epinastine, cetirizine, azelastine, and fexofenadine. (fexofenadine), levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene ), clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate , diphenhydramine, isoproterenol, ebastine, desloratidine, and meclozine, as required, as racemic isomers, Enantiomeric, diastereomeric forms, and optionally in the form of their pharmaceutically acceptable acid addition salts, solvates or hydrates. According to the present invention, the acid addition salts are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, decane sulfonate, nitrate, Maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate. Inhalable macromolecules as disclosed in European Patent No. 1,003,478 can also be used. In addition, the compounds may be derived from a group of ergot alkaloid derivatives, triptans, CGRP-inhibitors, phosphodiesterases _ 119201.doc -30- 200815059 v inhibitors, as needed It is in the form of an enantiomer or diastereomer of the exo-/exo-β-isomer, and it is an acid addition salt, a solvate and/or Or in the form of a hydrate. Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine. Suitable substances for inhalation include pharmaceutical compositions, pharmaceutical formulations and mixtures having the above-described active substances, and their salts, and the combination of such active substances f, salts and esters.

The pharmaceutical preparation may additionally contain standard commercially available suspending (IV) I adjuvants, surfactants and/or stabilizers. BRIEF DESCRIPTION OF THE DRAWINGS Other advantages, features, characteristics and aspects of the present invention will become apparent from the following description of the preferred embodiments of the invention. Figure 2 shows a nozzle tube with reduced dead volume; Figures 3 and 4 show a nozzle tube with optimally reduced dead volume (in all shapes, the suction according to the invention) Mouth); Figure 5: shows a nozzle tube as shown in Figure la but with reference numerals. In all cases, the drawing labeled "a" shows a longitudinal section in a side view. In all cases, the drawings of the "b" are used to illustrate the longitudinal section in a plan view. In the drawings, the same numbers are used for the same or similar parts having corresponding or equivalent features and advantages, even if the corresponding description is not repeated. [Main component symbol description] H9201.d〇 (-31- Spray vertical tube metering valve stem stem stem socket nozzle stem passage nozzle hole nozzle opening • 32-

Claims (1)

200815059 Patent application scope: 1. A device for providing a medicinal active substance, an active substance mixture and a formulation, the device comprising a container filled with a medical preparation and a valve comprising a pressurized liquefaction 1112_tetrafluoroethane (HFC-134a) or 1·1·1·2.3·3·3_ heptafluoropropane (hfc_227) 4HFC> An active substance, active substance mixture or formulation in a mixture of 134a and HFC-227, the valve being configured to deliver a single dose of a pharmaceutical formulation out of the device, the device characterized in that the nozzle tube of the device has one: There is also little or no dead volume channel (8). 2. The device of claim 1, wherein the pharmaceutical preparation further comprises a suspension adjuvant, a surfactant, and/or a stabilizer. 3. Apparatus according to claim 1 or 2, characterized in that the channel (8) is connected via a nozzle opening (9) to a nozzle opening (丨〇) having a funnel-shaped configuration. 4. The device of claim 1 or 2, characterized in that the nozzle hole has a diameter of 〇 2-0.6 mm. 5. The device of claim 1 or 2 for administering a pharmaceutical preparation comprising an anti-cholinergic drug, a betamimetic, a steroid, a diesterase-inhibiting Agents, anti-allergic agents and EGFR-kinase inhibitors, anti-allergic agents, ergot alkaloid derivatives, triptans (tnptan), CGRP-antagonists, phosphodiesterase-V- Inhibitors and combinations of such active substances. 6. Apparatus according to claim 1 or 2, characterized in that the nozzle opening is constructed in accordance with Figure 3 or 4. 119201.doc 200815059 7·- a nozzle tube, which is composed of a vertical tube (2), a valve stem socket (5), a nozzle hole (9) and a nozzle (6), the nozzle tube system Holding a metered dose spray to surround the nozzle tube (2) around the metered dose spray (1), the stem socket (5) of the nozzle tube closing the valve stem of the metering valve (3) (4) to form a seal, and having a passage (8), wherein the actual nozzle hole (9) is pressed against it at an obtuse angle with respect to its vertical axis, thus liquefying under pressure The pharmaceutical composition, mixture or formulation is deflected from the vertical downwardly disposed opening of the valve stem (7) > And through the nozzle hole (9) to the outside 'by the nozzle hole (9) to the nozzle opening. A transitional cloud is created at the transition of ❹), characterized in that the passage (8) has no or almost no dead volume. The nozzle tube of the month 7 is characterized in that the passage (8) is connected to a nozzle opening (1) of a funnel-shaped structure via a spray main (,,). 0. The nozzle tube of item 7 or 8 is characterized in that the nozzle hole (9) has a diameter. ;,Have 119201.doc